West Nile Virus (WNV) is an emerging mosquito-borne flavivirus that causes fatal outbreaks of encephalitis in Europe, Asia, the Middle East and the United States of America. Using genetically deficient mice we recently demonstrated that a deficiency of the complement components C1q or C4 leads to a disseminated, fatal WNV infection. Based on these observations, we propose to directly determine how activation of the classical and lectin complement pathways inhibits WNV infection. These results may be applicable to other related NIAID Category A and B flavivirus human pathogens.